tbuckley/cabot-search huggingface dataset:
CTNI-14. NEOADJUVANT STEREOTACTIC RADIOSURGERY (NASRS) FOR LARGE BRAIN METASTASES (BRM): RESULTS OF AN INTERNATIONAL MULTICENTER PHASE II TRIAL
Authors: David Shultz, Dianna Li, Ruth Lau Rodriguez, Randa Higazy, Normand Laperriere, Barbara-Ann Millar, Tatiana Conrad, Gelareh Zadeh, Aristotelis Kalyvas, Carolin Senger, Gueliz Acker, Julian Spears, Paul Kongkham
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND We conducted an international multi-center phase II trial evaluating NASRS for BrM. We hypothesized that radiation necrosis (RN) would be lower than post-operative cavity radiotherapy since the tissues receiving the highest radiation dose are resected in NASRS. METHODS BrM patients with 1 index lesion ( &amp;gt;2 and &amp;lt;5 cm in greatest diameter) suitable for resection, and 9 or less additional BrM (&amp;lt; 3 cm in greatest diameter, not requiring resection) were recruited across 3 centres. SRS was administered a median 3 (range: 2-21) days prior to surgical resection. A single fraction of 15-21 Gy was delivered, targeting the index tumor with a 2mm margin. From a sample of 30 patients, the primary endpoint was the 1-year rate of grade 2+ (G2+) RN from the index lesion. Secondary endpoints included local failure (LF), leptomeningeal disease (LMD) and overall survival (OS). RESULTS We enrolled 35 patients [Mean age (SD): 58.9 (12.9) years, 46% female] between 2018 and 2022. The most common primary histologies were lung (40%), and gastrointestinal (20%) cancers. The median BrM volume prior to surgery was 16.6 cc (range 3.2 -38.0); median index lesion size was 3.2 (range: 1.9-4.5) cm. All participants received planned protocol treatment; n = 30 are currently available for 1 year outcomes. No patients developed G2+ RN; 5 had a LF (1-year rate 38%) at 5-12-months following surgery, all of whom had an en-bloc resection. One patient each developed classic LMD and pachymeningeal failure 3 and 11 months after surgery, respectively. Median OS was 11.5 months. CONCLUSION No patients in our study experienced G2+ RN. The 1-year rate of LF was higher than anticipated, indicating the potential benefit of considering a higher radiation dose or larger margins for improved outcomes.
NCMP-21. AQP4-MOG DOUBLE-POSITIVE PARANEOPLASTIC NEUROLOGICAL SYNDROME IN A PATIENT WITH TRIPLE NEGATIVE BREAST CANCER
Authors: Amna Siddiqui, Dylan Ross, Ronak Jani, Vikram Prabhu, Shelly Lo, Derek Wainwright, Stasia Rouse, Tamer Refaat, Yirong Zhu, Jigisha Thakkar
Journal: Neuro-Oncology (2023)

Abstract We report a rare case of paraneoplastic neurological syndrome (PNS) with dual seropositivity of anti-aquaporin-4 (AQP-4) and myelin oligodendrocyte glycoprotein (MOG) antibodies in a 40 year-old lady with metastatic triple negative breast cancer with involvement of mediastinal, right axillary, and supraclavicular lymph nodes. She received multiple lines of anti-neoplastic treatment including immunotherapy with pembrolizumab as well as chemotherapy with taxol, carboplatin, gemcitabine, capecitabine, cytoxan, sacituzumab and nevalbine. Paraneoplastic meningoencephalomyelitis developed 2 years after diagnosis of breast cancer and 1 year after discontinuation of immunotherapy with pembrolizumab. She first developed longitudinally extending transverse myelitis extending from T11-12 that symptomatically improved with high dose intravenous methylprednisolone. One month later she developed left optic neuritis and meningoencephalitis with new enhancing lesions in the brain and spinal leptomeninges. Cerebrospinal fluid (CSF) analysis during both episodes revealed normal glucose, protein, elevated white blood cell count. Cytology was negative for malignancy. CSF was positive for neuromyelitis optica (NMO) IgG antibody APQ-4 and autoimmune myelopathy panel was positive for MOG antibody. Patient had significant clinical and radiographic improvement after completion of plasmapheresis and intravenous immunoglobulin. There was resolution of pleocytosis on repeat CSF testing. She did not have recurrence of paraneoplastic syndrome with maintenance rituximab every six months and daily low dose prednisone. She succumbed to progressive systemic metastatic disease 4.5 years after her breast cancer diagnosis. This case demonstrates that these antibodies can occur concurrently and cause clinical features like both neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD) in a patient with a singular type of cancer. We highlight the importance of testing for paraneoplastic etiology in cancer patients with radiographic menigoencephalomyelitis or meningitis with atypical symptoms of meningeal carcinomatosis and/or CSF profile negative for leptomeningeal carcinomatosis.
EPCO-39. CLARIFYING THE MOLECULAR CONSEQUENCES OF ONCOGENIC MUTATIONS THROUGH MULTISCALE AND MULTIOMIC ANALYSIS OF INDIVIDUAL TUMORS
Authors: Patrick Schupp, Samuel Shelton, Daniel Brody, Rebecca Eliscu, Brett Johnson, Tali Mazor, Kevin Kelley, Matthew Potts, Michael McDermott, Eric Huang, Daniel Lim, Russell Pieper, Mitchel Berger, Joseph Costello, Joanna Phillips, Michael Oldham
Journal: Neuro-Oncology (2023)

Abstract Understanding the molecular consequences of oncogenic mutations is an important goal that may reveal essential features of malignant cells and new therapeutic targets for diverse cancers. However, this task is complicated by substantial inter- and intra-tumoral heterogeneity, which obscure the molecular consequences of oncogenic mutations in malignant cells. Although single-cell methods hold promise for this task, it remains non-trivial to isolate DNA and RNA from the same cell at scale. Here we describe a statistically motivated strategy that controls for inter-tumoral heterogeneity and exploits intra-tumoral heterogeneity to reveal the most consistent molecular phenotypes of malignant cells. By combining deep, multiscale sampling of IDH-mutant astrocytomas with integrative, multiomic analysis, we reconstruct and validate the phylogenies, spatial distributions, and molecular profiles of distinct malignant clones. Importantly, by genotyping nuclei for driver mutations, we show that existing strategies for inferring malignancy from gene expression profiles of single cells may be inaccurate. We identify genes that are consistently upregulated in the truncal clone of IDH-mutant astrocytomas, which are significantly enriched with genes involved in RNA splicing, mRNA transport and the nuclear pore, and WNT / MYC signaling. Furthermore, we find that expression phenotypes of malignancy persist despite loss of the mutant IDH1 protein following chr2q deletion in a subset of malignant cells. More broadly, our work provides a generalizable strategy for precisely deconstructing intra-tumoral heterogeneity and determining the most robust molecular consequences of oncogenic mutations in any kind of solid tumor.
EXTH-55. ALL-IN-ONE GENETIC CONSTRUCT TO KNOCKDOWN MIR-21 REDUCES GLIOMA PROLIFERATION IN VITRO
Authors: Lisa Nieland, Anne Vrijmoet, Alexandra de Reus, Benjamin Kleinsteiver, Marike Broekman, Xandra Breakefield, Erik Abels
Journal: Neuro-Oncology (2023)

Abstract Glioma, the most aggressive tumor of the CNS has poor patient outcome with limited effective treatments. CRISPR-CAS technology recently opened a new avenue for gene therapy and has been previously used to target non-coding RNAs, including microRNA-21, an oncogene associated with glioma progression. Here we show that an all-in-one construct containing both Staphylococcus Aureus Cas9 (SaCas9) guided by a single-guide RNA (sgRNA) specifically targeting miR-21 resulted in a deletion causing a downregulation of miR-21 expression levels and reduced proliferation in glioma cell lines. Here, we aim to design a single adeno-associated vector (rAAV) vector platform that express both saCas9 and sgRNA to target miR-21 in a glioma syngeneic mouse model. With the future goal to engineer a single AAV that can achieve therapeutic genome editing outcomes.
SURG-15. RIGHT FRONTAL-PARIETAL PILOCYTIC ASTROCYTOMA WHO GRADE I ASSOCIATED WITH HEMORRHAGIC COMPONENT AND ESSENTIAL HYPERTENSION IN AN ADULT
Authors: Larrey Kamabu, Joel Kiryabwire
Journal: Neuro-Oncology (2023)

Abstract Pilocytic astrocytoma (PA) is a primary glial neoplasm and low-grade tumor. After total resection, the prognosis is very good. A poor prognosis results from leptomeningeal spreading and bleeding, both of which are extremely uncommon in Pilocytic Astrocytoma patients. Case presentation We report the case of a 43-year-old male that presented with a 4 days’ history of right sided frontal headache, non-radiating and mostly felt in the morning. Not associated with vomiting and fever. In addition, there was a sudden decline in level of consciousness with no associated stool or urine incontinence. The patient also developed three episodes of tonic clonic convulsions, lasting less than 3 minutes associated with urine incontinence and frothing from the mouth. Two days later, there was a sudden onset of left sided weakness involving upper and lower limbs. However, there is no history of trauma or hypertension. He was identified as having a hemorrhagic right frontal-parietal PA evidence on MRI associated with essential hypertension. The patient had an intervention combination of medical treatment and craniotomy via fronto-temporal approach plus excision of lesion. Histopathological examination of specimen determined that it was PA WHO grade I. He was treated with oral anti-epileptic therapy (Phenytoin 300 mg once a day), folic acid supplementation (400 mcg once a day), anti-hypertensive therapy (Amlodipine 10 mg and Losartan 50 mg once daily) and he showed marked improvement and was discharged home after 1 month and followed up by primary neurosurgeon, oncologist and physician. CONCLUSION: This case report raises awareness of Pilocytic Astrocytoma among adults and emphasizes the value of early diagnosis and management of patients with Pilocytic Astrocytoma associated with essential hypertension can prevent complications, reduce morbidity and mortality.
RADT-38. DOSE ESCALATED RADIOTHERAPY IS ASSOCIATED WITH IMPROVED OUTCOMES FOR HIGH GRADE MENINGIOMA
Authors: K Liang Zeng, Hany Soliman, Sten Myrehaug, Chia-Lin Tseng, Jay Detsky, Hanbo Chen, Mary-Jane Lim-Fat, Mark Ruschin, Eshetu G Atenafu, Julia Keith, Nir Lipsman, Chris Heyn, Pejman Maralani, Sunit Das, Farhad Pirouzmand, Arjun Sahgal
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The optimal modern radiotherapy (RT) approach after surgery for atypical and malignant meningioma is unclear. We present results of dose-escalation. METHODS Consecutive patients with histopathologic grade 2 or 3 meningioma treated with RT were reviewed. A dose-escalation cohort [≥ 66Gy equivalent dose in 2 Gy fractions using an a/b = 10 (EQD2)], was compared to a standard dose cohort (&amp;lt; 66Gy). Outcomes were progression-free survival (PFS), cause-specific survival (CSS), overall survival (OS), local failure (LF) and radiation necrosis. RESULTS 118 patients (111 Grade 2, 94.1%) were identified; 54/118 (45.8%) received dose-escalation and 64/118 (54.2%) standard dose. Median follow-up was 45.4 months (IQR: 24.0 - 80.0 months) and median OS was 9.7 years (Q1: 4.6 years, Q3: not reached). All dose-escalated patients had residual disease vs. 65.6% in the standard dose cohort (p &amp;lt; 0.001). PFS at 3-, 4- and 5-years in the dose-escalated vs. standard dose cohort were 78.9%, 72.2% and 64.6% vs. 57.2%, 49.1% and 40.8%, respectively, (p = 0.030). On multivariable (MVA) analysis, dose-escalation (HR: 0.544,p = 0.042) was associated with improved PFS, whereas ≥ 2 surgeries (HR: 1.989, p = 0.035) and older age (HR: 1.035, p &amp;lt; 0.001) were associated with worse PFS. The cumulative risk of LF was reduced with dose-escalation (p = 0.016). MVA confirmed dose-escalation protective for LF (HR: 0.483, p = 0.019), whereas ≥ 2 surgeries prior to RT predicted for LF (HR: 2.145, p = 0.008). A trend was observed for improved CSS and OS in the dose-escalation cohort (p &amp;lt; 0.1). Seven patients (5.9%) developed symptomatic radiation necrosis (RN) with no significant difference between the two cohorts. CONCLUSIONS Dose-escalated radiotherapy with ≥ 66Gy for high grade meningioma is associated with improved local control and PFS with an acceptable risk of RN.
RTID-07. A RANDOMIZED WINDOW OF OPPORTUNITY TRIAL WITH DOSE ESCALATION TO EVALUATE FLUOXETINE AND TEMOZOLOMIDE IN GLIOMA
Authors: Kirit Singh, Chelsea Railton, Kelly Hotchkiss, James Herndon, Katherine Peters, Henry Friedman, Annick Desjardins, David Ashley, Margaret O Johnson, Anoop Patel, Allan Friedman, Michael Lim, Peter Fecci, David Piccioni, Tresa McGranahan, Seema Nagpal, Erik Sulman, Paul Mischel, Mustafa Khasraw
Journal: Neuro-Oncology (2023)

Abstract The blood brain barrier limits the efficacy of many drugs in brain tumors. Fluoxetine (Prozac) is FDA-approved and brain penetrant. Preclinical studies show synergy between fluoxetine and temozolomide (TMZ), resulting in lysosomal stress and enhanced DNA damage in human-derived glioma in vitro and in vivo. We present our randomized surgical window of opportunity trial (NCT05634707) in patients with recurrent IDH wild type glioma. The primary objective is to evaluate if fluoxetine induces tumoral lysosomal stress while exploratory objectives will determine if combination therapy enhances tumor DNA damage. We will randomize 30 patients, ≥ 24yo, with recurrent glioma and who are eligible for re-treatment with TMZ (MGMT methylated, progression &amp;gt;6 months post TMZ). Following informed consent, patients will be randomized 1:2 to control or experimental arms. Control patients will receive 50 mg/m2 TMZ for 7 days pre-resection. The experimental arm will receive 20 mg/day fluoxetine for 5 days before escalating to 40 mg/day. If &amp;lt; 3/10 participants receiving 40mg/day experience dose-limiting toxicity (DLT), subsequent experimental arm patients will escalate to 60 mg/day. All experimental arm participants will receive 50 mg/m2 TMZ for 7 days after starting fluoxetine, starting 21 days pre-resection. The regimen of 50 mg/m2 TMZ for 7 days is based on a similar pre-surgical trial combining TMZ with experimental therapy (NCT05188508). This reduced dose was chosen to limit potential synergistic toxicities like thrombocytopenia or neutropenia. Following resection, patients will continue TMZ, initially at reduced dose for the first post-op cycle, before reverting to standard doses of 150-200mg/m2 (up to 12 cycles or progression). All patients (control and experimental) will be offered fluoxetine post-operatively. The primary study outcome will be quantification of tumoral lysosomal stress via Lysosomal-associated membrane protein 1 (LAMP1) expression while DNA damage will be assessed via γH2A histone family member X (γH2AX) using immunohistochemistry.
EPCO-42. A SYSTEMS SCALE MODEL FOR PERSONALIZED PRECISION ONCOLOGY APPLICATIONS TO GBM
Authors: Serdar Turkarslan, Yu He, Parvinder Hothi, Carl Murie, Abran Nicolas, Kavya Kannan, James H Park, Min Pan, Anoop Patel, Charles Cobbs, Nitin S Baliga
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is the most aggressive and lethal type of brain tumor, and its treatment remains challenging due to the complexity of the underlying molecular mechanisms. Here, we present gbmMINER, a causal and mechanistic transcriptional regulatory network model for GBM that integrates multi-omics and clinical data with a new network quantization approach using the MINER algorithm. gbmMINER accurately grouped 9,728 genes into 3,797 regulons and identified 179 transcriptional programs that stratify GBM into 23 disease states, associated with distinct clinical outcomes. We demonstrate that the activity profiles of regulons and programs in the quantized network model accurately predict overall survival, identifying patients with significantly longer OS of up to 42 months. Through extensive characterization using independent cohort datasets and genome-wide CRISPR screening data, we demonstrate the accuracy of gbmMINER in delineating causal and mechanistic insights into well-known and novel prognostic somatic mutations in GBM. Finally, through high-throughput drug screening, we demonstrate that the activity of regulons and programs accurately predicts the sensitivity of patient-derived glioma stem-like cells (PD-GSCs) to anticancer drugs. In theory, gbmMINER could be implemented to better stratify patients based on prognosis and potentially identify precision therapeutic strategies based on network activity.
TMIC-01. PERICYTES ORCHESTRATE A TUMOR-SUPPRESSIVE MICROENVIRONMENT BY IMPINGING ON THE CROSSTALK BETWEEN MACROPHAGES AND TUMOR-INITIATING CELLS IN GLIOBLASTOMA MULTIFORME
Authors: Sebastian Braun, Clara Oudenaarden, Paulina Bolivar, Jonas Sjölund, Eugenia Cordero, Rebecca Rosberg, Elinn Johansson, Alexander Pietras, Kristian Pietras
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma multiforme (GBM) is characterized by fast progression, infiltrative growth pattern and a high rate of relapse. A defining feature of GBM is the existence of spatially and functionally distinct cellular niches, i.e. a hypoxic niche, a leading-edge niche, and a peri-vascular niche, in which malignant cells engage in paracrine crosstalk with cell types comprising the tumor microenvironment, including immune cells, astrocytes, and vascular cells. Here, by analysis of single-cell transcriptomic data of human GBM and transgenic mouse models of GBM, we unexpectedly identified pericytes intimately associated with the endothelium as the most active paracrine signaling hub within the tumor parenchyma. Exclusive signaling axes emanating from pericytes were received by endothelial cells, malignant cells, astrocytes, and immune cells. Depletion of pericytes through genetic engineering in several different transgenic and orthotopic mouse models of GBM demonstrated accelerated tumor progression, a disrupted blood-brain-barrier, and premature death of pericyte-poor mice. Mechanistic studies revealed that pericyte deficiency altered the cellular composition of GBM, remodeled the endothelium, and impacted on the immune cell landscape. Specifically, endothelial cells deprived of pericyte association upregulated Colony Stimulating Factor (CSF)-1, which in turn attracted peri-vascular tumor-associated macrophages polarized towards an immune-suppressive phenotype. In the absence of pericytes, the recruited macrophages expressed Hepatocyte Growth Factor (HGF), which reinforced activation of its receptor tyrosine kinase c-Met on a subset of GBM cells harboring an extreme mesenchymal-like state. Indeed, orthotopic implantation of isolated c-Met-expressing GBM cells corroborated their superior tumor-initiating capability and invasive phenotype, compared to cells negative for c-Met. Taken together, we infer that the pericyte represents a critical modulator of GBM development by orchestrating a tumor-suppressive microenvironment; our findings thus highlight the importance of pericyte preservation in the face of current and future GBM therapies.
NIMG-50. TOTAL TUMOR CELLULARITY AND CELLULAR GROWTH RATES ESTIMATED USING A RADIO-PATHOMIC AI MODEL PREDICTS PROGNOSIS AND RESPONSE TO CYTOTOXIC THERAPY IN RECURRENT GBM
Authors: Sonoko Oshima, Jingwen Yao, Samuel Bobholz, Raksha Nagaraj, Catalina Raymond, Ashley Teraishi, Anna-Marie Guenther, Asher Kim, Francesco Sanvito, Nicholas Cho, Blaine Eldred, Jennifer Connelly, Whitney Pope, Phioanh Nghiemphu, Albert Lai, Noriko Salamon, Timothy Cloughesy, Peter LaViolette, Benjamin Ellingson
Journal: Neuro-Oncology (2023)

Abstract PURPOSE A radio-pathomic machine learning model trained with postmortem tissue samples has recently been developed to estimate tumor cellularity from standard anatomic MR images (Bobholz SA et al. AJNR 2022). The aim of this study was to use this externally developed, machine learning-based model to assess the impact of tumor cellularity and changes in cellularity on survival in recurrent glioblastoma (rGBM) treated with standard cytotoxic therapies. METHODS We retrospectively evaluated 22 cases of rGBM treated with chemotherapy. Radio-pathomic maps of predicted tumor cellularity were generated using the radio-pathomic model using pre- and post-contrast T1-weighted MR images, T2-weighted FLAIR images and apparent diffusion coefficient calculated from diffusion-weighted imaging. Total cellularity was estimated by integrating the cellularity measures within a contrast-enhancing tumor volume of interest. Cellularity growth rates (CGRs) were computed using three pre-treatment scans and available post-treatment scans. Tumor cellularity and CGRs were assessed in terms of their impact on overall survival (OS) using log-rank analysis. RESULTS Patients with baseline tumor cellularity &amp;lt; 8.89x108 cells and those with pre-treatment CGR &amp;lt; 7.55x106 cells/day showed significantly longer OS than those with higher cellularity or CGRs (P = 0.001 and 0.008, respectively). Patients with cellularity &amp;lt; 8.90x108 cells at the 1st follow-up (one month after treatment), those with cellularity at 2nd follow-up &amp;lt; 8.89x108 cells (two months after treatment), post-treatment CGR &amp;lt; 1.51x107 cells/day, and change in CGR after treatment &amp;lt; +5.91x106 cells/day showed significantly longer OS than those with higher values (P = 0.03, &amp;lt; 0.001, &amp;lt; 0.001, = 0.02, respectively). CONCLUSION These preliminary results suggest the potential value of estimating total cellularity within the enhancing tumor as a biomarker for prognosis prediction and cytotoxic therapy effect evaluation in rGBM. Additional analyses with more cases and treatments are warranted.
SURG-43. SURGICAL TREATMENT FOR SPINAL CORD HEMANGIOBLASTOMA - DIFFERENCE IN SURGICAL INDICATION FROM CEREBRAL HEMANGIOBLASTOMA
Authors: Shunsaku Takayanagi, Hirokazu Takami, Shota Tanaka, Nobuhito Saito
Journal: Neuro-Oncology (2023)

Abstract Objective Spinal cord hemangioblastoma (HB) is a tumor with abundant blood flow with feeders and drainers, and is often accompanied by large cysts and syringomyelia. About 25% of HB cases are said to be von Hippel-Lindau (VHL) disease cases, which is a hereditary tumor disease. In VHL disease, multiple surgeries are often performed because HB occurs frequently. To consider whether spinal cord HB requires a different surgical indication from brain HB cases, this report analyzed the treatment results of HB cases at our hospital. Methods From 1988 to 2021, 85 patients with HB underwent surgery at our hospital investigated. Results There were16 cases of spinal cord, 58 of cerebellum, and 10 of brainstem. Of these, 46 cases (13 families, 21 patients) had VHL disease. There were 13 cases (81%) with syringomyelia and 8 cases (50%) with cysts in spinal cord HB. The mean tumor volume at spinal cord, cerebellum and brainstem were 3.2, 15.9 and 5.8 cm3, respectively. Changes in mRS before and after surgery were as follows; spinal cord HB: improvement 10 (63%)/deterioration 3 (19%), cerebellar HB: improvement 35 (60%)/deterioration 7 (12%), brainstem HB: improvement 7. (70%)/0 deterioration. In spinal cord HB, total resection was achieved in all cases, and no significant complication was observed. Conversely, 12 patients (17%) underwent shunting for postoperative hydrocephalus in cerebellum/brain stem HB. In spinal cord HB, no local recurrence was observed during the follow-up period of median 54 months (4-188 months). Conclusion Spinal cord HB was operated when the tumor volume was smaller than that of brain HB, but there was no significant difference in the symptom improvement rate. However, there were a certain number of patients who deteriorated after surgery, and it was thought that further analysis would be necessary in the future regarding appropriate surgical indications for spinal cord HB.